Trauma in the adult mammalian central nervous system (CNS) results in devastating clinical consequences due to the failure of injured axons to spontaneously regenerate. Chondroitin sulphate proteoglycans (CSPGs) and the myelin-associated inhibitors (MAIs) myelin-associated glycoprotein (MAG) (McKerracher et al., 1994; Mukhopadhyay et al., 1994), Nogo-A (Chen et al., 2000; GrandPre et al., 2000; Prinjha et al., 2000) and Oligodendrocyte-myelin glycoprotein (OMgp) (Kottis et al., 2002; Wang et al., 2002) bind receptor molecules on injured axons initiating intracellular signaling cascades which block axonal regrowth (Mandemakers and Barres, 2005). In part, CSPGs and MAIs inhibit axon regeneration by disrupting Rho-GTPase-dependent cytoskeletal dynamics. Blockade of RhoA and a downstream effector Rho kinase (ROCK) promotes axon regeneration both in vitro and in vivo (Dergham et al., 2002; Borisoff et al., 2003; Fournier et al., 2003); however, the ability of RhoA and ROCK to affect multiple physiological processes in many cell types (Riento and Ridley, 2003) highlights the need to identify novel intracellular signaling substrates of neurite outgrowth inhibition to develop more specific and potent therapeutic avenues.
The CRMPs are a family of cytosolic phosphoproteins with five vertebrate family members (CRMP1-5) (Goshima et al., 1995; Minturn et al., 1995; Byk et al., 1996; Gaetano et al., 1997; Inatome et al., 2000). CRMP1-4 alleles each produce two transcripts, a and b, and CRMPb variants are longer amino terminal variants of the originally identified CRMPa isoforms (Yuasa-Kawada et al., 2003). Although CRMPs share significant sequence similarity with dihydropyrimidinase (DHPase), an enzyme involved in pyrimidine catabolism, no DHPase activity has been described for CRMPs (Wang and Strittmatter, 1997). Rather, a role for CRMPs in axon growth and pathfinding has been revealed. CRMPs are homologs of UNC-33, a protein that influences axon guidance and extension in C. elegans (Hedgecock et al., 1985; Siddiqui and Culotti, 1991). CRMP2 mediates growth cone collapse in response to the repulsive guidance cue Semaphorin3A (Goshima et al., 1995), and CRMP2 and CRMP4 influence neurite outgrowth (Minturn et al., 1995; Quinn et al., 1999; Quinn et al., 2003; Yoshimura et al., 2005). Mechanistically, CRMP2 can bind to tubulin heterodimers and organizes microtubule assembly to establish axon-dendrite fate during development (Fukata et al., 2002b; Arimura et al., 2005) and CRMP4 can promote F-actin bundling (Rosslenbroich et al., 2005). Further, a role for CRMP2 in endocytosis has been described (Nishimura et al., 2003) and an association between CRMP4b and intersectin, an endocytic-exocytic adaptor protein, is consistent with an endocytic role for this isoform (Quinn et al., 2003).
The role of the CRMP proteins in nervous system injury and regeneration has not been extensively studied; however CRMP2a does have a potent neurite elongating effect in nerve regeneration in vivo (Suzuki et al., 2003). CRMP1a, CRMP2a and CRMP5a mRNA levels increase after hypoglossal nerve injury and CRMP4a expression is increased in regenerating adult sciatic motor neurons (Minturn et al., 1995; Suzuki et al., 2003) suggesting a more general role for CRMP proteins in the neuronal response to injury.